URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers.

Abstract Tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) has only limited clinical benefit and reaches a bottleneck due to its drug resistance. Here, through whole transcriptome sequencing (RNA-Seq) and lipidomic analysis, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, we find that p53 binds to the promoter of stearoyl-CoA desaturase 1 ( Scd1) and represses its transcription. Therefore, high expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in xenografted models of wild-type p53 liver cancer cell lines. This combination therapy has potential significant clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.